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Background and aims: Hepatitis C virus (HCV) genotyping is a pivotal tool for epidemiological investigation, guiding management and antiviral treatment. Challenge existed in identifying subtypes of genotype-1 (G-1) and genotype (GT) of indeterminate. Recently, the Abbott HCV RealTime Genotype Plus RUO assay (HCV GT Plus) has been developed aiming to overcome the limitations. We aimed to evaluate the performance of the assay compared with 5' UTR sequencing in clinical samples. Materials and methods: Eligible individuals were treatment chronic hepatitis C patients that were enrolled consecutively in a medical center and two core regional hospitals in southern Taiwan from Oct 2017 through Aug 2018. The patient with genotype 1 without subtype and indeterminate previously genotyped by Abbott RealTime HCV GT II will further determinate by Abbott HCV RealTime HCV GT Plus. All of the genotype results were validated by 5' UTR sequencing as a reference standard. Results: A total of 100 viremic CHC patients were recruited, including 63 G-1 patients (male: 28), and 37 patients (male: 15) of indeterminate genotyped by Abbott RealTime HCV GT II assay (HCV GT II), respectively. The detection rate of 63 GT1 samples without subtype were 93.7% (59/63), 37 indeterminate samples without genotype were 62.2 (23/37) by HCV GT Plus. 5' UTR sequencing confirmed HCV GT Plus characterized results for 84.7% (50/59) of type1, with 100% (4/4), 82.8 (24/29) and 84.6% (22/26) for 1a, 1b and type6; 65.2% (15/23) of indeterminate with 100% (3/3) and 60% (12/20) for 1b and type 6 samples, respectively. Conclusions: The Abbott RealTime HCV GT Plus RUO assay provides additional performance in GT detection. [ABSTRACT FROM AUTHOR]

Both dengue virus (DENV) and hepatitis C virus (HCV) belong to the Flaviviridae family and could induce hepatitis. We aimed to investigate the interference between them. In total, 515 patients confirmed with dengue fever (DF) were enrolled. Thirty-two patients (6.21%) were seropositive for anti-HCV; 12 of 32 anti-HCV-positive patients had detectable HCV-RNA at presentation of DF. The proportion of dengue hemorrhagic fever was comparable between patients with or without anti-HCV and between those with or without HCV-RNA. Eleven of 32 patients received HCV-RNA testing during a median interval of 23 months after DF, which revealed significantly increased HCV-RNA levels (5.43 ± 0.77 vs 3.09 ± 1.24 log IU/mL, follow-up vs acute-DF phase; P  = .003). Four of 11 patients with baseline HCV-RNA values before DF demonstrated a nadir viremia during acute DF. We also included age-, sex-, and follow-up duration–matched HCV-monoinfected patients as controls; higher delta HCV-RNA changes were demonstrated in patients with DF than in controls during the follow-up period (2.34 ± 1.15 vs –0.27 ± 0.76 log IU/mL; P  < .001). Further in vitro experiments showed that HCV nonstructural protein 5A was downregulated in Con1 HCV replicon cells infected by DENV1. These clinical and experimental findings suggested possible viral interference in DENV/HCV. However, HCV viremia did not affect the disease outcomes of DF. [ABSTRACT FROM AUTHOR]

Background: Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) was a novel marker of liver fibrosis. We aimed to investigate WFA+-M2BP level in assessing liver fibrosis in patients with chronic hepatitis B (CHB) infection. Methods: A total of 160 CHB patients, who received a liver biopsy, were consecutively recruited. Serum WFA+-M2BP level was quantified at the time point of biopsy. The results were compared with histopathological manifestations and clinical characteristics of the patients. Results: The median WFA+-M2BP level, aspartate aminotransferase-to-platelet ratio (APRI) and Fibrosis-4 (FIB-4) index were 1.20 COI, 1.19, and 1.63, respectively. Fifty-one (31.9%) patients had advanced fibrosis. There was a significant increase of WFA+-M2BP levels in parallel to necroinflammation/fibrosis stages. The areas under the receiver operating characteristic curve (AUROC) of WFA+-M2BP level for predicting fibrosis stages were 0.780 of F2, 0.785 of F3, and 0.769 of F4, respectively (all p <0.001). The multivariate analysis identified age (Odds ratio [OR] 1.05, 95% confidence interval [CI]: 1.010–1.092, p = 0.014), platelet (OR: 0.99, 95%CI: 0.980–0.998, p = 0.013), and WFA+-M2BP level (OR: 1.97, 95% CI: 1.299–2.984, p = 0.001) as independent factors associated with advanced fibrosis. Combination of age, platelet and WFA+-M2BP level achieved a better diagnostic performance for advanced fibrosis (AUROC: 0.732, accuracy: 81.3%) than APRI (AUROC: 0.577, accuracy: 63.8%) or FIB-4 index (AUROC: 0.691, accuracy: 75.6%). Conclusion: WFA+-M2BP had a good performance indistinguishing liver fibrosis in CHB patients. The combination of age, platelet, and WFA+-M2BPaddressed more accuracy in identifying patients with advanced fibrosis. [ABSTRACT FROM AUTHOR]

Aim 25-Hydroxy vitamin D (Vit D) plays a role in treatment outcomes in chronic hepatitis C virus (HCV) infection. We aimed to clarify whether HCV replication is inhibited by Vit D in HCV replicon cells. Clinical implication was assessed for rapid virological response (RVR) and sustained virological response (SVR) among those patients receiving antiviral therapy. Methods Cell survival and viral loads were observed in Con1 (genotype 1b) and J6/JFH (genotype 2a) cells treated with different doses of Vit D. Three groups of patients with different treatment responses were recruited to assess their Vit D levels: group A, RVR−/SVR−; group B, RVR+/SVR−; and group C, RVR+/SVR+. Results The viral load of Con1 cells decreased by 69%, 80%, and 86% following treatment with 1 μM, 5 μM, and 10 μM Vit D, respectively ( P < 0.0001). In J6/JFH cells, it decreased by 12%, 55%, and 80.5% following treatment with 1 μM, 5 μM, and 10 μM Vit D, respectively ( P < 0.0001). There was a significant increase of Vit D between chronic hepatitis C groups, ranging from 4.4 ± 5.6 ng/mL in group A ( n = 44), to 17.2 ± 11.6 ng/mL in group B ( n = 44), and 32.5 ± 37.5 ng/mL of group C ( n = 44) ( P < 0.001). Advanced fibrosis (odds ratio = 0.13, 95% confidence interval = 0.04-0.41, P < 0.001) and Vit D deficiency (<10 ng/mL) (odds ratio = 0.11, 95% confidence interval = 0.03-0.43, P = 0.001) were predictive of SVR in the multivariate regression analysis. Conclusion Vitamin D decreases HCV replication and also contributes to early treatment viral kinetics. [ABSTRACT FROM AUTHOR]

Background & aims: Identification of disease severity remains a challenge in the management of non-alcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18), is a recently developed non-invasive biomarker for NASH. We aimed to assess the performance of CK18 in disease severity prediction among Taiwanese NASH patients. Methods: A total of 76 biopsy-proven NASH patients (54 males, age = 41.0 ± 13.5 years) were consecutively recruited. The optimal cutoff values of CK18 for each stage of fibrosis were correlated with their histopathological manifestations. Results: There were 23 (30.3%) patients of Metavir fibrosis stage 0 (F0), 32 (42.1%) patients of F1, 14 (18.4%) patients of F2, and 7 (9.2%) patients of F3-4, respectively. The CK18 levels among those patients of F0, F1, F2, F3-4 were 86.7 ± 75.6 U/L, 122.4 ± 123.8 U/L, 160.7 ± 120.4 U/L, and 507.3 ± 343 U/L, respectively (trend for P<0.001). The adjusted optimal cutoff value for F2 prediction was 312.5 U/L, yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the accuracy of 96.4%, 28.6%, 77.9%, 75%, and 77.6%, respectively (P = 0.009). For the prediction of advanced fibrosis (F3-4), the adjusted optimal cutoff value was 374.5 U/L, yielding the sensitivity, specificity, PPV, NPV, and the accuracy of 97.1%, 54.1%, 95.7%, 66.7%, and 77.6%, respectively (P = 0.003). Among those patients without hyperuricemia, the PPV, NPV, and accuracy of CK18 reached 100%, 95.8%, and 96%, respectively (P<0.001). Conclusions: CK18 combined with uric acid measurement is a promising non-invasive biomarker for prediction of disease severity in NASH patients. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background & Aims: Asians are more susceptible to non-alcoholic steatohepatitis (NASH) as well as metabolic disorder than other ethnicities. We aimed to assess the interaction between metabolic factors and fibrosis in Taiwanese NASH patients. Methods: A total of 130 biopsy-proven Taiwanese NASH patients (94 males, age = 43.0 ± 13.0 years) were consecutively enrolled. Their demographic, metabolic profiles and histopathological manifestations were analyzed. Results: Twenty-four (18.5%) NASH patients were non-obese. Thirty-three (25.4%) patients had significant fibrosis (F2) or more: 22 (16.9%) patients were of F2, whilst 11 (8.5%) patients were of advanced fibrosis (F3-4). The prevalence of metabolic syndrome, diabetes and hypertension were 60.8%, 39.4%, and 61.5%, respectively. There was a significant inverse correlation between hyperuricemia and fibrosis stages, ranging from 48.4% of F0-1, 33.3% of F2, and 9.1% of F3-4, respectively (P = 0.01, linear trend). Multivariate logistic regression analysis showed that a decreased serum albumin level (OR = 40.0, 95% CI = 4.5–300, P = 0.001) and normal uric acid level (OR = 5.6, 95% CI = 1.5–21.7, P = 0.01) were the significant factors associated with significant fibrosis. Conclusions: Hyperuricemia inversely predicts fibrosis stages. Females might carry a more disease severity than males in Taiwanese NASH patients. [ABSTRACT FROM AUTHOR]

Background and Aim Chronic hepatitis C virus ( HCV) infection has been suggested to be associated with non-insulin-dependent diabetes mellitus and lipid profiles. This study aimed to investigate the possible relationships of insulin resistance ( IR) and lipid profiles with chronic hepatitis C ( CHC) patients in Taiwan. Methods We enrolled 160 hospital-based CHC patients with liver biopsy and the 480 controlled individuals without CHC and chronic hepatitis B from communities without known history of non-insulin-dependent diabetes mellitus. Fasting plasma glucose, total cholesterol, high-density lipoprotein cholesterol ( HDL- C), low-density lipoprotein cholesterol ( LDL- C), triglycerides ( TGs), alanine aminotransferase, and serum insulin levels, and homeostasis model assessment ( HOMA-IR) were tested. Results When comparing factors between CHC patients, and sex- and age-matched controls who had no HCV infection, patients with HCV infection had a significantly higher alanine aminotransferase level, fasting plasma glucose level, insulin level, and HOMA-IR ( P < 0.001, P = 0.023, P = 0.017, and P = 0.011, respectively), and significantly lower TG level ( P = 0.023), total cholesterol, and HDL- C and LDL- C levels (all P < 0.001) than 480 controls. In multivariate logistic regression analyses, a low total cholesterol, a low TGs, and a high HOMA-IR are independent factors significantly associated with chronic HCV infection. In the 160 CHC patients (41 patients with high HOMA-IR [> 2.5]), a high body mass index, TGs, and HCV RNA level are independent factors significantly associated with high HOMA-IR in multivariate logistic analyses. Conclusions Chronic HCV infection was associated with metabolic characteristics including IR and lipid profile. IR was also associated with virological characteristics. [ABSTRACT FROM AUTHOR]

Background/Aims Pre-diabetes is a risk factor for type 2 diabetes mellitus ( DM) development. This study aimed to elucidate the impact of treatment response on sequential changes in glucose abnormalities in pre-diabetic chronic hepatitis C ( CHC) patients. Methods Chronic Hepatitis C patients with a baseline haemoglobin A1 C ( A1 C) range 5.7-6.4% who achieved 80/80/80 adherence were prospectively recruited. All patients received current peginterferon-based recommendations. The primary outcome measurement was their A1 C level at the end of follow-up ( EOF). The interaction between variants of the IL28 B gene and outcomes of glucose metabolism was also measured. Results A total of 181 consecutive CHC patients were enrolled. The mean A1 C at EOF was 5.82 ± 0.41%, which was significantly lower than the baseline level (5.93 ± 0.21%, P < 0.001). At EOF, 63 (34.8%) patients became normoglycaemic, whereas 10 (5.5%) patients developed DM. The sustained virological response ( SVR) rates of 63 normoglycaemics, 108 pre-diabetics and 10 diabetic patients at the EOF were 92.1%, 84.3% and 50% respectively (normoglycaemics vs. diabetics P = 0.003; pre-diabetics vs. diabetics P = 0.02). Achievement of an SVR was the only predictive factor associated with normoglycaemia development at EOF by multivariate logistic regression analysis (Odds ratio = 2.6, P = 0.04). The prevalence of the interleukin 28 B rs8099917 TT variant in patients who developed DM (70.0%) at EOF tended to be lower than that in patients with pre-diabetics (87.0%) or normoglycaemics (92.1%). Conclusion Successful eradication of HCV improves glucose abnormalities in pre-diabetic CHC patients. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) proteins can activate the PI3K/Akt pathway which is involved in multiple cellular functions such as inflammatory cell activation and liver fibrosis. The aim of the present study was to elucidate the correlation between Akt expression and liver fibrosis staging in chronic hepatitis C (CHC) patients. Paraffin-embedded liver sections from 133 consecutive treatment-naïve CHC patients were recruited. The expression features of Akt were analyzed using immunohistochemical methods and the results were compared with histological, virological and biochemical profiles. The 73 patients with high Akt expression carried higher histological activity index scores (6.52 ± 2.5 vs 5.62 ± 2.4, P = 0.04) and advanced fibrosis (72.7% vs 26.3%, P < 0.01) than other 60 patients with low Akt expression. The high Akt expression showed a significant incremental trend dependent on fibrosis stages, from 33.3% of F0 to 85.7% of F4 ( P = 0.005). Akt expression was not correlated with degrees of steatosis and virological features of HCV infection, such as viral load and genotypes. Multivariate logistic regression analysis showed advanced fibrosis was the most significant factor associated with high Akt expression (odds ratio = 3.16). Hepatic Akt expression correlated with advanced liver fibrosis in CHC patients. [ABSTRACT FROM AUTHOR]

Detection and quantification for hepatitis B virus (HBV) DNA has been an essential tool in the clinical setting. We aimed to assess clinical performance of the RealArt HBV TM PCR (RealArt) assay and the COBAS TaqMan HBV (COBAS) assay. Serum levels of HBV DNA in 146 treatment-naive chronic HBV (CHB) Taiwanese patients (118 males, 47 HBeAg + ; mean age, 34.7±13.0 y) were determined by both assays. The detection rate by the RealArt assay was 85.6% (125/146), which was not significantly different from the COBAS assay (89.7%, 131/146). The detection rate was also not significantly different between both assays irrespective of HBeAg seropositivity. The 2 assays were also comparable regarding quantification rate (92.8%, 116/125 vs 93.1%, 122/131). There was a positive correlation in the 109 specimens measurable by both assays (r=0.94, p<0.001). The mean HBV DNA level measured by the COBAS assay was significantly higher than the RealArt assay (5.24±1.83 vs 4.79±2.09 log IU/ml, p<0.001). This study demonstrated that both RealArt and COBAS assays were comparable regarding clinical performance in HBV DNA measurement. [ABSTRACT FROM AUTHOR]

Background/Aims: Insulin resistance (IR) might be associated with hepatitis C virus (HCV) infection. This study aimed to elucidate impact of IR and beta-cell function on the response to peginterferon-alpha (PEG-IFN)/ribavirin combination therapy in chronic hepatitis C (CHC) patients. Methods: Three hundred and thirty patients without overt diabetes were treated with combination therapy with (PEG-IFN)/ribavirin for 24 weeks. The IR and beta-cell function were evaluated by homeostasis model assessment of IR (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-beta) before treatment. Results: HCV genotype, pretreatment HCV RNA level and pretreatment HOMA-IR, but not HOMA-beta, were independent factors associated with sustained virologic response (SVR). In 150 patients with genotype 1b infection, pretreatment HCV RNA level, HOMA-IR and age were independent predictors for SVR. The significantly lower SVR rate in high HOMA-IR patients was observed in 76 patients with high HCV RNA levels (⩾400,000IU/mL) who were defined as ‘difficult-to-treat’ patients. The mean HOMA-IR of ‘difficult-to-treat’ patients was significantly lower in 42 sustained responders than in 34 non-responders. Conclusions: IR was associated with SVR to (PEG-IFN)/ribavirin therapy for CHC, especially among ‘difficult-to-treat’ patients. These findings suggested clinical application of pretreatment HOMA-IR could enable treatment outcome to be predicted and treatment regimens to be determined. [Copyright &y& Elsevier]

Background/Aims: Hepatitis C virus (HCV) infection carries a significant risk for development of insulin resistance (IR) and/or diabetes mellitus. Recently, retinol-binding protein 4 (RBP4) has been reported as a protein contributing to IR. This study aimed to assess the correlation between RBP4 and disease severity of chronic HCV infection (CHC). Methods: Serum RBP4 was measured in 105 treatment-naı¨ve CHC patients and its correlation with the homeostasis model assessment of insulin resistance index (HOMA-IR), liver histology, virology and metabolic factors was investigated. Patients were stratified into different stages of glucose tolerance by oral glucose tolerance test. Results: There was a significant decreasing linear trend of RBP4 dependent on both histological grading (from 35.8±16.5μg/mL of minimal to 19.2±12.5μg/mL of severe, P =0.002) and staging (from 34.2±10.0μg/mL of F0 to 22.2±11.9μg/mL of F3-4, P =0.02) progression, whilst a significant increment of HOMA-IR was found. Multivariate regression analysis showed BMI (1.1, 95% CI 0.44∼1.77, P =0.001), HDL-C (−0.40, 95% CI −0.73∼−0.06, P =0.02), and LDL-C (0.31, 95% CI 0.02∼0.61, P =0.04) were the significant variables for prediction of RBP4. Conclusions: Disease severity may limit the role of RBP4 as a predictor of IR in CHC. [Copyright &y& Elsevier]

OBJECTIVES: There is growing evidence suggesting the mutual link between type 2 diabetes mellitus (T2DM) and hepatitis C virus (HCV) infection. However, the impact of HCV infection on the suite of glucose abnormalities has rarely been investigated. The study aimed to determine the difference regarding the prevalence and the characteristics of glucose abnormalities between chronic hepatitis C (CHC) patients and community-based controls. It also aimed to investigate the related clinical, virological, and histological features of glucose abnormalities in HCV infection. METHODS: Six hundred eighty-three CHC patients and 515 sex-/age-matched controls were included. Oral glucose tolerance test (OGTT) was performed in 522 CHC patients and 447 controls without known T2DM. Clinical data were assessed upon the different stages of glucose abnormalities based on OGTT results. RESULTS: The prevalence of normoglycemia, IGT, and T2DM in 683 CHC patients was 27.7%, 34.6%, and 37.8%, respectively. There was a significant linear trend from normoglycemia to T2DM in terms of age, family history of T2DM, and advanced liver fibrosis in CHC patients. For those CHC patients without fibrosis, the prevalence of glucose abnormalities reached 67.9% high. All CHC patients carried a significantly higher prevalence than controls regarding those aged <65 yr. For those without known DM, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%) (OR 3.51, 95% CI 2.70–4.56, P < 0.001). CONCLUSIONS: CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested. [ABSTRACT FROM AUTHOR]

Abstract Background To elucidate the incidence of the rare cases of icteric type hepatocellular carcinoma (IHCC), we conducted a retrospective study. The clinical outcomes of IHCC cases were also analyzed. Methods From January 1986 to December 1997, newly diagnosed HCC cases were evaluated and reviewed from an admission registration database in a medical center. Patients who had HCC tumors which were located within biliary tracts, and caused obstructive jaundice as the initial clinical manifestation of HCC, were defined as cases of IHCC. Besides clinical manifestations, the outcomes and survival times of various treatment strategies among the IHCC cases were compared retrospectively. Results The incidence of IHCC was 0.53% (10/1897). The median age of the 10 IHCC patients (seven men, three women) was 56.1 years (range = 41–72 years). Most primary HCC lesions (80%) were of expansive type: either single nodular type or multinodular type. All the patients eventually died of cholangitis and sepsis. Besides biliary drainage, seven patients of moderate to good liver reserve function received transarterial chemoembolization (TACE) for palliative treatment, and three of these received additional radiotherapy (R/T) because of the limited effect of TACE (total dosage ranged from 1600 to 5000 cGy). One patient received only radiotherapy (total dosage 1600 cGy) because of having a single tumor and poor liver reserve function. The median survival time among those eight patients who received palliative treatment was 13.4 months (range = 8–26 months), which was significantly longer than for the other two patients without treatment (2 and 4 months). Conclusions Icteric type hepatocellular carcinoma (IHCC) is a rare presentation of HCC. Palliative treatment strategies, including TACE and/or R/T showed a beneficial effect in improving the survival time. [ABSTRACT FROM AUTHOR]